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One-on-One with Tier One: Dr. Seema Khurana

Dr. Seema Khurana (left middle) and her lab work with the protein villin.

What do breast cancer and colon cancer have in common? Actually, they may have a lot more in common than you might think. Studying a potential link through a protein called Villin is Dr. Seema Khurana. Khurana, professor in the University of Houston’s Department of Biology and Biochemistry, has recently received an award of $1.8 million from the National Institutes of Health (NIH) to study Villin and its potential connection to certain types of cancer. She sat down with UH’s Division of Research (DOR) to talk about her work and its potential impact to cancer treatment.

DOR: How did you get started in your research?

SK: When I was an assistant professor at Johns Hopkins University, I made an interesting observation about a protein called Villin, which is expressed at very high levels in the epithelial cells specifically. Villin is not seen in all cell types. At that time, it was thought that Villin was a bundling protein, which means it takes actin, a structural component of the cell, and forms a chemical chain within the cell. I had data at that time that suggested that Villin actually did the opposite: it disassembled the actin filaments. At that time, the thinking was that Villin could only polymerize and crosslink, although scientists knew from test tube studies, in vitro, that this protein could do both polymerization and depolymerization. However, in vitro studies in the lab are not always reflective of actual in vivo function. I had data that suggested that even in the body it could function in both ways. In the end, my discovery ended up becoming the currently accepted theory.

DOR: Can you describe how your research relates to cancer research?

Two of Khurana’s lab members study cultures on an agar plate.

SK: Well, I’ve been interested in a certain kind of cell known as epithelial cells, which are a kind of stationary cells that, among other places, exist in the gastrointestinal tract. Oddly, over 90 percent of cancers that are lethal originate from epithelial cells. If the tumor is stationary, a surgeon can just go and remove it; however, one of the more morbid parts of cancer is that those cells start moving. Therefore, that brings up two main questions: first, why do so many of these lethal cancers come from epithelial cells, which are inherently stationary cells? Why doesn’t cancer spread through cells that already have the ability to move such as fibroblasts? Secondly, what causes that cell to move and spread? What are the triggers? Figuring out the regulation of metastasis is enormously difficult.

DOR: How might metastasis be happening in these epithelial cells?

SK: One thing scientists think regulates metastasis in most epithelial cancers is that they undergo a genetic reprogramming. It’s almost like a masquerade. The epithelial cell tries to become like a mesenchymal cell, another kind of cell, which has the ability to move. It is not just that it now looks like a mesenchymal cell, but we think that it actually goes through an entire genetic reprogramming to become a mesenchymal cell. If it’s ‘losing’ epithelial genes and ‘gaining’ mesenchymal genes, the thinking is that it is doing this through down-regulation and up-regulation of genes, kind of like turning down the speed or up the speed on a conveyor belt. Either you are essentially making less or more of a protein or proteins and that regulation dramatically changes the environment and the actions of a cell. This is what is called EMT, or epithelial-mesenchymal transition, and it is a key focus of our study.

DOR: So how does Villin relate to colorectal cancer?

SK: Well, we made another interesting observation. Scientists think that Villin is a protein that stays in the cytosol, or the liquid found inside a cell. We saw that always a small fraction goes into the nucleus. We did many experiments to make sure that it was not an artifact of the way we were imaging or collecting data. We found that our results were real; a small portion of Villin goes into the nucleus. It does not just go in and stay there. It also goes in and out dynamically.

For sterile research, many labs use hoods to protect their samples from contamination.

I have a collaborator in Australia who has an extensive collection of cell samples from patients with colorectal cancer. When I showed him my data, he offered to screen those cells. He found that in patients with colorectal cancer, about five percent had cells with nuclear expression of Villin. Five percent is quite substantial. This tells us that there is a subset of colorectal patients who have this abnormality.

DOR: What was the next step from there?

SK: So while this was a novel discovery, we needed to find a real significance for this. While trying to figure this out, we modified Villin so that it would not go into the nucleus or only go to the nucleus and stay in the nucleus. Because we are able to control the movement, we think there is some regulation of this trafficking in and out of the nucleus. We think it is regulated by the enzyme Src kinase, which has been implicated in several cancers, particularly also in colorectal cancer. As we did more screening for regulation of this trafficking of Villin in and out of the nucleus of the cell, we identified a special protein that has previously been implicated in breast cancer cells called ZBRK1 or ZNF350.

DOR: What is the significance of ZBRK1 or ZNF350?

SK: While we don’t know a lot about Villin’s role in colorectal cancer, there is sufficient data that shows the function of ZBRK1 in the regulation of another gene that is important in breast cancer that many may know about, the BRCA 1 gene, which is a gene that produces a protein with anti-cancer properties. Mutations or misregulation of BRCA1 are said to increase your risk factor for breast and ovarian cancer. ZBRK1 is known to regulate BRCA 1 gene. Our current thinking is that there is subgroup of colorectal cancer patients in whom the BRCA 1 and ZBRK1 genes are abnormally regulated like in breast cancer patients, and, in colorectal cancer, the abnormal regulation of these genes is mediated by Villin trafficking to the nucleus. We have this hypothesis and many data supporting it; we think is pretty profound. NIH thought so too, and this grant was funded recently as you know.

Our long-term goal is to translate our findings into clinical outcomes to diagnose and/or prevent colon cancer. Modulation of EMT has tremendous therapeutic advantages since EMT is reversible and because antagonism of EMT has been shown to repair injured tissue. So we think like many others that regulation of EMT offers novel therapeutic targets to inhibit diseases like fibrosis but also to diagnose and treat cancer patients. We hope that manipulation of Villin, ZBRK1, and BRCA 1 to alter gene expression could be a viable target for rational design of a new generation of novel drugs. These new therapies could specifically target these pathways and lead to individualized treatment. In fact, we could even use the nuclear trafficking of Villin to deliver therapeutic DNA or drugs to the nucleus in some sort of gene therapy to treat not just cancers but also other diseases in which abnormal EMT is implicated, such as in chronic kidney disease or Inflammatory Bowel Disease.

DOR: Would you say that cancers are less related by in which tissue they occur?

SK: Oh yes, I think so. We’re seeing less and less treatment being targeted at the type of tissue and more about a certain molecular signature. This makes the therapy more individualized. It’s a more nuanced method, and a method that is causally relating cancers rather than relating them by location.

I think our research will allow for this classification and acceptance at a larger level that this is not just one odd case for colon cancer, that it is true for many different kinds of cancers.